Education
- Post-Doc: Neurobiology; UCLA; 1981
- PhD: UCLA; 1980
Background
Dr. Hammer obtained a PhD in anatomy and conducted postdoctoral studies in neurobiology at UCLA before becoming a Staff Fellow, then Senior Staff Fellow in the Intramural Research Program at the National Institute of Mental Health in Bethesda, Maryland. In 1984, he became Associate Professor of Anatomy and Pharmacology at the University of Hawaii School of Medicine, where he taught gross anatomy and medical neuroscience, and rose to the rank of Professor in 1993. He received a Research Career Development Award from the National Institute of Neurological Disorders and Stroke in 1987, and was Visiting Associate Research Anatomist at UCLA from 1987-1993. In 1994, he moved to Tufts University School of Medicine, where he was Professor of Psychiatry, Anatomy, Pharmacology and Neuroscience, and Director of the Laboratory of Research in Psychiatry. He served as Course Director for Addiction Medicine and Psychopathology courses, taught Medical Neuroscience and Medical Pharmacology, and served as Associate Dean for Educational Affairs at Tufts University School of Medicine from 1998-1999. He also held an appointment as Lecturer on Psychiatry at Harvard Medical School, and Visiting Scientist in the Alcohol and Drug Abuse Research Center at McLean Hospital from 1994-2006. In 2006, he moved to Phoenix as Professor of Basic Medical Sciences at the University of Arizona College of Medicine.
Research
My laboratory studies plasticity and neural adaptation in mesocorticolimbic systems. We have focused on the nucleus accumbens (NAc) due to its involvement in addiction and certain symptoms of schizophrenia (i.e., sensorimotor gating deficits), but we are currently developing strategies for elucidating caudate dysfunction which may afford a more unified model of etiology in schizophrenia. Furthermore, the lack of plasticity and consequent behavioral rigidity which this model attributes to caudate dysfunction are common features of other neuropsychiatric disorders, such as autism, obsessive-compulsive disorder and Tourette syndrome. This work is interdisciplinary, involving cellular and molecular neurobiology and neuropsychopharmacology, and translational by nature, permitting the extension of our basic research findings into potential therapies for neuropsychiatric disorders.
Selected Publications
Intermittent social defeat stress enhances mesocorticolimbic ΔFosB/BDNF co-expression and persistently activates corticotegmental neurons: implication for vulnerability to psychostimulants Nikulina EM, Lacagnina MJ, Fanous S, Wang J, Hammer RP Jr. Neuroscience. 2012 Jun 14;212:38-48. Epub 2012 Apr 19. PMID: 22521816
Viral depletion of VTA BDNF in rats modulates social behavior, consequences of intermittent social defeat stress, and long-term weight regulation. Fanous S, Terwilliger EF, Hammer RP Jr, Nikulina EM. Neurosci Lett. 2011 Sep 20;502(3):192-6. Epub 2011 Aug 4. PMID: 2183914
Sensitized activation of Fos and brain-derived neurotrophic factor in the medial prefrontal cortex and ventral tegmental area accompanies behavioral sensitization to amphetamine. Fanous S, Lacagnina MJ, Nikulina EM, Hammer RP Jr. Neuropharmacology. 2011 Sep;61(4):558-64. Epub 2011 May 5. PMID: 2157099
cAMP response element binding protein phosphorylation in nucleus accumbens underlies sustained recovery of sensorimotor gating following repeated D₂-like receptor agonist treatment in rats. Berger AK, Green T, Siegel SJ, Nestler EJ, Hammer RP Jr. Biol Psychiatry. 2011 Feb 1;69(3):288-94. Epub 2010 Oct 30. PMID: 21035786
Short- and long-term effects of intermittent social defeat stress on brain-derived neurotrophic factor expression in mesocorticolimbic brain regions. Fanous S, Hammer RP Jr, Nikulina EM. Neuroscience. 2010 May 19;167(3):598-607. Epub 2010 Mar 3. PMID: 2020623
Genomic survey of prepulse inhibition in mouse chromosome substitution strains. Leussis MP, Frayne ML, Saito M, Berry EM, Aldinger KA, Rockwell GN, Hammer RP Jr, Baskin-Hill AE, Singer JB, Nadeau JH, Sklar P, Petryshen TL. Genes Brain Behav. 2009 Nov;8(8):806-16. Epub 2009 Jul 21. PMID: 1969481
Long-lasting alteration in mesocorticolimbic structures after repeated social defeat stress in rats: time course of mu-opioid receptor mRNA and FosB/DeltaFosB immunoreactivity. Nikulina EM, Arrillaga-Romany I, Miczek KA, Hammer RP Jr. Eur J Neurosci. 2008 May;27(9):2272-84. PMID:
Swerdlow, N.R., A.S. Krupin, M,J. Bongiovanni, J.M. Shoemaker, J.C. Goins and R.P. Hammer: Heritable differences in the dopaminergic regulation of behavior in rats: Relationship to D2-like receptor G protein function, Neuropsychopharmacology, 31(4): 721-729, 2006
Petryshen, T.L., A. Kirby, R.P. Hammer, A. Hill, J. Singer, J. Nadeau, M.J. Daly and P. Sklar: Two QTLs for prepulse inhibition of startle on mouse chromosome 16 using chromosome substitution strains, Genetics, 171:1895-904, 2005 .
Culm, K.E., N. Lugo-Escobar, B.T. Hope and R.P. Hammer: Repeated quinpirole treatment reverses sensorimotor gating deficits by increasing cAMP-dependent protein kinase activity and CREB phosphorylation in nucleus accumbens, Neuropsychopharmacology, 29: 1823-1830, 2005.
Covington H.E., T. Kikusui, J. Goodhue, E.M. Nikulina, R.P. Hammer and K.A. Miczek: Brief social-defeat stress: persistent changes in cocaine taking during binges and zif268 mRNA expression in the amygdala and prefrontal cortex, Neuropsychopharmacology, 30: 310-321, 2005.
Nikulina E.M., K.A. Miczek and R.P. Hammer: Prolonged effects of repeated social defeat stress on mRNA expression and function of µ-opioid receptors in the ventral tegmental area of rats, Neuropsychopharmacology, 30: 1096-1103, 2005.
Miczek K.A., H.E. Covington, Nikulina E.M., and R.P. Hammer: Aggression and defeat: Persistent effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits, Neuroscience and Biobehavioral Reviews, 27: 287-802, 2004.
Nikulina E.M., H.E. Covington, J. Goodhue, L. Ganschow, R.P. Hammer, and K.A. Miczek: Long-term behavioral and neuronal cross-sensitization to amphetamine induced by repeated brief social defeat stress: Fos in the ventral tegmental area and amygdala, Neuroscience, 123: 857-865, 2004.
Culm, K.E. and R.P. Hammer: Recovery of sensorimotor gating deficits without G protein adaptation after chronic dopamine D2-like receptor agonist treatment, Journal of Pharmacology and Experimental Therapeutics, 308:487-494, 2004.
Culm, K.E., A. Lim, J.A. Onton, and R.P. Hammer: Reduced Gi and Go protein function in the nucleus accumbens attenuates sensorimotor gating deficits, Brain Research, 982: 12-18, 2003.
Hammer, R.P.: Neural circuitry and signaling in addiction, pp. 99-124 in: G.B. Kaplan and R.P. Hammer (eds.), Brain Circuitry and Signaling in Psychiatry; Basic Science and Clinical Implications, American Psychiatric Publishing, Inc., 2002.
Research
My laboratory studies plasticity and neural adaptation in mesocorticolimbic systems. We have focused on the nucleus accumbens (NAc) due to its involvement in addiction and certain symptoms of schizophrenia (i.e., sensorimotor gating deficits), but we are currently developing strategies for elucidating caudate dysfunction which may afford a more unified model of etiology in schizophrenia. Furthermore, the lack of plasticity and consequent behavioral rigidity which this model attributes to caudate dysfunction are common features of other neuropsychiatric disorders, such as autism, obsessive-compulsive disorder and Tourette syndrome. This work is interdisciplinary, involving cellular and molecular neurobiology and neuropsychopharmacology, and translational by nature, permitting the extension of our basic research findings into potential therapies for neuropsychiatric disorders.
Molecular and genetic substrates of neuropsychiatric disorders
Our recent studies examine mechanisms underlying sensorimotor gating deficits which are altered by stress or drug treatment. Sensorimotor gating deficits underlie thought disorder and sensory flooding in patients with schizophrenia, and they can be rigorously quantified in human and animal subjects by measuring prepulse inhibition of acoustic startle responses. We discovered that repeated treatment with selective dopamine D2-like receptor agonists completely reverses sensorimotor gating deficits in rats. Furthermore, functional recovery lasts for weeks after termination of treatment, and blocks deficits produced by phencyclidine and other non-competitive NMDA receptor antagonists. The mechanism underlying recovery involves heterologous sensitization of cAMP signaling in the NAc; we observed up-regulation of cAMP-dependent protein kinase (PKA) and enhanced phosphorylation of the transcription factor cAMP response element binding protein (CREB), which is required for recovery of sensorimotor gating. We also used adeno-associated viral gene transfer to determine that deltaFosB expression in NAc neurons is necessary for recovery of sensorimotor gating. Further characterization is ongoing to determine how this subset of neurons causes or reverses behavioral symptoms.
Sensorimotor gating deficits also serve as an endophenotype amenable to genetic analysis. We utilized prepulse inhibition to determine putative sensorimotor gating genes in consomic (chromosome substitution) mouse strains in collaboration with colleagues at the MIT/Harvard Broad Institute. Thus far, we have identified chromosome 16 as a putative locus, along with two genes that are differentially expressed and map to a suggestive sensorimotor gating QTL in consomic mice. One of these is the D3 receptor gene, supporting our hypothesis that D3 receptor-related neuroadaptation regulates recovery of sensorimotor gating.
Neuronal and neurochemical effects of stress and psychostimulant drugs
Various reinforcing drugs as well as stress exposure are known to induce dopamine release in the NAc. We have shown that repeated exposure to a salient social stressor in rats leads to the development of sensorimotor gating deficits, and is associated with induction of FosB expression in NAc, amygdala and limbic frontal cortex. We have shown that
We plan to investigate the causative influence of this persistent cortical Fos expression on NAc dopamine by overexpression of δFosB or a dominant negative inhibitor of δFosB under the control of a tetracycline-regulated gene expression system. These and other persistent changes in specific forebrain circuits may represent the substrate by which stress triggers the onset or relapse of schizophrenia symptoms in humans.
Repeated exposure to a salient social stressor in rats causes behavioral cross-sensitization to psychostimulants. We showed that chronic social stress exposure induces transient expression of functional mu-opioid receptors in the ventral tegmental area which increases mesolimbic dopamine tone. Further studies revealed that subsequent induction of brain-derived neurotrophic factor may underlie the eventual transition to long-lasting drug cross-sensitization. We are currently examining the selective intracellular signaling mechanism responsible for stress-induced cross-sensitization.
A cognitive neuroscience approach to schizophrenia
Neuroimaging studies of schizophrenia have identified deficits in various brain regions (e.g., prefrontal, temporal and occipital cortex), hippocampus, thalamus, striatum, and others. The diversity of these regions and the breadth of cognitive deficits in schizophrenia suggests a pervasive disorder. Alternatively, a more parsimonious explanation might be that deficits in critical striatal neurochemistry could alter neural response to produce widespread symptoms.
We are developing a testable model of caudate involvement in positive symptoms of schizophrenia. The basis of this model is that limbic, motor and cognitive striatum are connected via parallel circuits which originate and terminate in various cortical regions. Just as putamen regulates the initiation of motor activity and the generation of motor patterns, we propose that caudate regulates the initiation of cognitive activity (i.e., thoughts) and generation of cognitive patterns (i.e., beliefs). Thus, dysfunction caused by excessive dopamine in caudate may lead to abnormal thoughts or beliefs related to specific cortical regions, thereby producing hallucinations or delusions, the hallmarks of psychosis. Furthermore, reduced glutamatergic stimulation of caudate would enhance this effect, and deficient glutamate-associated plasticity would promote behavioral rigidity and "fixed" cognitive patterns observed in schizophrenia. Ongoing experiments assess cortical response to intracranial manipulation of relevant receptors in rat caudate to demonstrate the putative substrate of these effects.